Network meta-analysis of targeted therapies for diffuse large B cell lymphoma

Background The purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma (DLBCL). Methods The PubMed, EmBase, and Cochrane library electronic databases were systematically searched throughout December 2019. Direct and indirect evidence from relevant RCTs was identified for network meta-analysis. The pooled results for grade 3 or greater adverse events between targeted therapies and chemotherapy were calculated using a random-effects model. Results A total of 18 RCTs enrolling 8207 DLBCL patients were selected for the final meta-analysis. The results of the network analysis indicated that the addition of dacetuzumab (74.8%) to rituximab-based regimens or lenalidomide (77.1%) was associated with better therapeutic effects on overall survival, whereas dacetuzumab (80.4%) or bortezomib (70.8%) added to rituximab was most likely to improve events-free survival. Moreover, lenalidomide (93.8%) and I-tositumomab (77.2%) were associated with higher overall response rates. Finally, patients receiving targeted therapies were associated with an increased risk of diarrhea (RR: 2.63; 95%CI: 1.18–5.86; P = 0.019), and thrombocytopenia (RR: 1.41; 95%CI: 1.05–1.90; P = 0.023). Conclusions This study provides the best treatment strategy for DLBCL patients in terms of overall survival, events-free survival, and overall response rate. The findings of this study require validation with further large-scale RCTs. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07715-2.


Background
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for nearly 30-35% of malignancy in all newly diagnosed B-cell lymphomas. It is characteristically aggressive and potentially curable [1]. Diffuse large B-cell lymphoma is heterogeneous in morphology, genetics, and clinical behavior, and its outcomes can be predicted by several prognostic scores [2][3][4]. Two major subtypes of DLBCL, germinal center B-cell-like (GCB) and activated B-cell-like (ABC), account for approximately 50 and 40% of DLBCL diagnoses, respectively [5][6][7]. However, the remaining 10-15% of DLBCL patients do not meet the criteria of either the GCB or the ABC subtype, and, combined with ABC DLBCL patients, can be regarded as non-GCB DLBCL patients [8].
Today, the addition of the monoclonal CD20 antibody rituximab to primary treatment regimens has greatly improved outcomes for DLBCL patients [9][10][11]. The longterm cure rate after rituximab-containing conventional chemotherapy regimens is > 80.0% in young patients with good prognoses [10]. Moreover, the prognoses for patients at intermediate to high risk according to the International Prognostic Index are also improved by similar chemoimmunotherapy regimens, whereas the therapeutic effects remain unsatisfactory for residual relapse risk patients [9]. Several other targeted therapies have already been introduced for DLBCL patients at various stages, but evidence on the therapeutic effects of these agents on the prognosis of DLBCL is both limited and inconclusive. Therefore, we attempted a large-scale examination of the available evidence to evaluate the best treatment option for DLBCL patients, and summarized the direct and indirect evidence comparing different agents using a network meta-analysis approach.

Search strategy and selection criteria
This meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology [12]. Throughout December 2019, we systematically searched the PubMed, EmBase, and Cochrane Central Register of Controlled trials databases with the following keywords: ("Diffuse large B cell lymphoma" OR "DLBCL") AND ("random" or "blind"). We also conducted manual searches of reference lists from all the relevant original and review articles to identify additional eligible studies.
The literature search and study selection were independently carried out by two authors, and any disagreement was resolved by a third author. Studies were included if the following inclusion criteria were met: (1) Patients: all patients were diagnosed with DLBCL; (2) Intervention: rituximab-, I-tositumomab-, bevacizumab-, bortezomib-, dacetuzumab-, ibrutinib-, ofatumumab-, obinutuzumab-, or lenalidomide-based treatment regimens were used; (3) Control: chemotherapy or rituximab-based chemotherapy was used as a control; (4) Outcomes: the primary outcomes were overall survival (OS), events-free survival (EFS), and overall response rate (ORR), while the secondary outcomes included any potential adverse events; and (5) Study design: all included studies had to have a randomized controlled trial (RCT) design. Exclusion criteria included basic studies and genotype-related studies. Further, reviews, editorials, letters, and conference papers without sufficient data were excluded.

Data collection and quality assessment
The following items were extracted from each study: first authors' surname, publication year, country, sample size, mean age, number of men and women, disease status, stage, intervention, chemotherapy regimen, and reported outcomes. The methodological quality of the included studies was assessed using the JADAD scale, which is based on the following five items: randomization, concealment of the treatment allocation, blinding, completeness of follow-up, and the use of intention-to-treat analysis [13]. Data extraction and quality assessment were conducted independently by two authors. Information was examined and adjudicated independently by an additional author referring to the original studies.

Statistical analyses
A network meta-analysis was conducted for indirect and mixed comparisons of various agents [14]. The loopspecific approach, which assesses the difference between direct and indirect estimates for a specific comparison in the loop, was employed to check for the presence of inconsistency [15]. A design-by treatment interaction inconsistency model was used to check the assumption of consistency across the entire network [14]. After this, an inconsistent model was employed due to the potential heterogeneity among included patients. The surface under the cumulative ranking (SUCRA) probabilities were calculated to rank the treatments for each outcome [16]. Publication biases for primary outcomes were calculated using comparison-adjusted funnel plots [17]. Moreover, the pooled results for potential grade 3 or greater adverse events were calculated using the relative risk (RR) with corresponding 95% confidence intervals (CI) using a random-effects model [18,19]. The potential impacts of disease status on the prognosis of DLBCL were also illustrated by subgroup analysis. Heterogeneity across included trials was calculated using the I 2 and Q statistics, and P < 0.10 was considered as significant heterogeneity [20,21]. A two-side p value < 0.05 was considered statistically significant for all analysis. All statistical analyses were performed using STATA (Version 10.0, Stata Corp., College Station, TX, USA).

Study characteristics
The baseline characteristics of the included studies are presented in Table 1. To summarize, the studies were published from 2002 to 2019, and 102-1418 patients were included in individual trials. Ten of the included studies were conducted in multiple countries, and the remaining eight studies were conducted in a single country. Mean age of included patients ranged from 47.0-69.5 years, and the disease status ranged from low to high risk. The quality of included studies was evaluated using the JADAD scale, and studies with a score of 4 or 5 were regarded as high quality. Overall, six studies scored 4, six studies scored 3, four studies scored 2, and the remaining two studies scored 1.

Overall survival
The eligible comparisons of OS in the network plot including I-tositumomab, bevacizumab plus rituximab, bortezomib plus rituximab, dacetuzumab plus rituximab, ibrutinib plus rituximab, lenalidomide, obinutuzumab, ofatumumab, and rituximab treatments are presented in Supplemental 1. The nodes and the edges are weighted based on the number of studies in each treatment and on the precision of the direct pair-wise comparison, respectively. The SUCRA probabilities (%) were ranked to obtain comparative effects of these agents on OS, and the results indicated that the addition of dacetuzumab (74.8%) to rituximab-based regimens and lenalidomide (77.1%) was the most likely to improve OS (Fig. 2). The results of pair-wise comparisons agents are presented in Supplementals 2 and 3. Finally, no significant publication bias was detected through reviewing the funnel plot (Supplemental 4).

Events-free survival
The eligible comparisons of EFS in the network plot including I-tositumomab, bevacizumab plus rituximab, bortezomib plus rituximab, dacetuzumab plus rituximab, ibrutinib plus rituximab, lenalidomide, obinutuzumab, ofatumumab, and rituximab are presented in Supplemental 1. The results of the SUCRA probabilities (%) indicated that dacetuzumab (80.4%) or bortezomib (70.8%) added to rituximab was the treatment most likely to improve EFS (Fig. 3). Supplementals 2 and 3 shows the details regarding the therapeutic effects of pair-wise comparisons agents on EFS. No significant publication bias was observed upon reviewing the funnel plot (Supplemental 4).

Overall response rate
The network meta-analysis comparing the effects of various agents including I-tositumomab, bevacizumab plus rituximab, bortezomib plus rituximab, dacetuzumab plus rituximab, ibrutinib plus rituximab, lenalidomide,  obinutuzumab, ofatumumab, and rituximab on ORR is presented in Supplemental 1. The SUCRA probabilities (%) indicated that lenalidomide (93.8%) produced the best therapeutic effect on ORR, and that I-tositumomab (77.2%) had a relatively good effect on ORR (Fig. 4). The results of pair-wise comparisons agents on ORR are listed in Supplementals 2 and 3. The funnel plot showed that there was no publication bias (Supplemental 4).

Traditional meta-analysis
We firstly noted targeted therapies are significantly associated with improved OS, irrespective for previous untreated patients  Table 2).

Discussion
The current network meta-analysis was carried out to compare the efficacy and safety of targeted therapies for DLBCL patients, and to investigate agents including Itositumomab, bevacizumab plus rituximab, bortezomib plus rituximab, dacetuzumab plus rituximab, ibrutinib plus rituximab, lenalidomide, obinutuzumab, ofatumumab, and rituximab. This comprehensive quantitative study included 8207 DLBCL patients from 18 RCTs across a broad range of patient characteristics. The findings of this study indicated that the addition of dacetuzumab to rituximab-based regimens or lenalidomide was associated with greater improvements in OS, while dacetuzumab or bortezomib added to rituximab had a relatively good effect on EFS. Furthermore, DLBCL patients receiving lenalidomide or I-tositumomab experienced better ORR. Moreover, targeted therapies present an increased risk of diarrhea and thrombocytopenia compared with traditional chemotherapy or rituximabbased chemotherapy regimens. This is the first meta-analysis to compare various targeted therapies for patients with DLBCL, whereas several other meta-analysis have provided the results for a single agent. A meta-analysis conducted by Lin et al. contained four studies and found that bortezomib-containing regimens did not yield significant improvements in survival outcomes, and might be associated with a greater risk of peripheral neuropathy compared to standard R-CHOP regimens [40]. Moreover, Ren et al. observed that rituximab salvage therapy was associated with better OS, PFS, and ORR for relapse or refractory DLBCL, whereas maintenance rituximab therapy did not significantly affect OS or  [41]. However, until now, no studies had compared the therapeutic effects of various agents for patients with DLBCL. Therefore, the current comprehensive network meta-analysis was conducted to elucidate the best treatment strategies for patients with DLBCL based on OS, EFS, and ORR.
The results of this study indicated that the addition of dacetuzumab to rituximab-based regimens or lenalidomide was associated with relatively good therapeutic effects on OS. However, the results of pair-wise comparisons indicated that dacetuzumab added to rituximabbased regimens or lenalidomide were associated with greater improvements in OS compared to chemotherapy, whereas no other significant differences between agents were observed. Moreover, dacetuzumab or bortezomib added to rituximab produced relatively good effects on EFS. One potential reason for this is that dacetuzumab directly affects malignant cells and antigen-presenting cells, especially dendritic cells [33]. Furthermore, DLBCL patients received lenalidomide or I-tositumomab experienced better therapeutic effects on ORR. Lenalidomide modulates CRL4 CRBN E3 ligase activity and the associating ubiquitination and subsequent proteasomal degradation of Aiolos and Ikaros, which could cause decreased proliferation of ABC-DLCBL cell lines and activation of immune cells such as T and natural killer cells [42,43].  Although the results of pair-wise comparisons were mostly not statistically significant, these results could be due to the small number of studies. The results of this study indicated that several treatments were associated with significant improvements in OS and EFS, without more severe adverse events occurring. However, the risk of diarrhea and thrombocytopenia in patients receiving targeted therapies was significantly increased. Moreover, the impact of the toxicity of targeted therapies on quality of life should be taken into account. However, a pooled conclusion on life quality was not drawn due to the fact that data on quality of life were rarely available, highlighting the need for further verification by largescale RCTs.
There were several limitations in our study. First, the results of this study are at the study level, not at the individual level. Second, the characteristics of enrolled patients varied, which could have affected their prognoses. Third, stratified analyses according to study or patient characteristics were not conducted because several treatments were reported in a smaller number of trials. Forth, the background treatment strategies were not addressed, which could have biased survival outcomes. Finally, the analysis was based on published articles, and publication bias is inevitable.

Conclusions
In conclusion, dacetuzumab to rituximab-based regimens or lenalidomide produces better effect on OS in DLBCL patients, while dacetuzumab or bortezomib added to rituximab is associated with greater improvements in EFS. Moreover, patients receiving lenalidomide or I-tositumomab have a relatively high ORR. Finally, patients receiving targeted therapies are at an increased risk of diarrhea and thrombocytopenia compared to those receiving traditional chemotherapy or rituximab-based chemotherapy regimens.